Cancer-specific collagen protects tumors
Research in the Kalluri Laboratory
Overview
Our laboratory is dedicated to unraveling the fundamental principles governing cancer initiation, progression and metastasis, with specific emphasis on tumor microenvironment. The efforts of the Kalluri laboratory since 1997 have led to many discoveries related to mechanism of tissue injury and regeneration, vascular biology and tumor angiogenesis, and tumor microenvironment and exosomes biology. Many of these findings have been translated into the clinic to benefit our patients. Discoveries in the Kalluri Laboratory unraveled new understanding of the biology of cancer, offered opportunities to work with pharmaceutical industry to develop new drugs, and contributed to the formation of new biotechnology companies. Areas of active inquiry are highlighted below.
Tumor Microenvironment in Cancer Biology and Metastasis
TSA multiplex imaging analysis of human PDAC tissue to identify 8 different tumor microenvironment components in a single paraffin section. © Nature Communications
The laboratory continues to generate new genetically engineered mouse models to determine the functional contribution of the tumor microenvironment in cancer progression and metastasis. Using such models, we recently identified a tumor restraining role of carcinoma associated fibroblasts, and discovered functional heterogeneity of fibroblasts in the progression of pancreatic cancer. We unraveled novel mechanisms of metastasis and identified the defining functional role of tumor microenvironment in rate of cancer progression. Current projects in the laboratory are evaluating the regulatory connection(s) between genetic drivers of cancer and the impact of host stromal and immune responses in cancer progression and metastasis. Employing genomic and epigenetic analyses, single cell RNA sequencing, mass cytometry and proteomic profiling, the laboratory is developing novel connectivity networks and unraveling nodes of regulation between genetic defects in the cancer cells, and stromal fibroblasts recruitment, tumor angiogenesis/hypoxia, and innate and adaptive immunity. Such integrated approach to cancer biology is identifying novel mechanism associated with tumor progression and metastasis, leading to the identification of new vulnerabilities of cancer and new avenues for drug development.
Relevant Publications:
- Folkman J, Kalluri R. Cancer without disease. Nature. 2004 Feb 26;427(6977):787. PMID: 14985739.
- Maeshima Y, Sudhakar A, Lively JC, Ueki K, Kharbanda S, Kahn CR, Sonenberg N, Hynes RO, Kalluri R. Tumstatin, an endothelial cell-specific inhibitor of protein synthesis. Science. 2002 Jan 4;295(5552):140-3. PMID: 11778052.
- Cooke VG, LeBleu VS, Keskin D, Khan Z, O'Connell JT, Teng Y, Duncan MB, Xie L, Maeda G, Vong S, Sugimoto H, Rocha RM, Damascena A, Brentani RR, Kalluri R. Pericyte depletion results in hypoxia-associated epithelial-to-mesenchymal transition and metastasis mediated by met signaling pathway. Cancer Cell 2012 Jan 17;21(1):66-81. PMID: 22264789.
- Özdemir BC, Pentcheva-Hoang T, Carstens JL, Zheng X, Wu CC, Simpson TR, Laklai H, Sugimoto H, Kahlert C, Novitskiy SV, De Jesus-Acosta A, Sharma P, Heidari P, Mahmood U, Chin L, Moses HL, Weaver VM, Maitra A, Allison JP, LeBleu VS, Kalluri R. Depletion of Carcinoma-Associated Fibroblasts and Fibrosis Induces Immunosuppression and Accelerates Pancreas Cancer with Reduced Survival. Cancer Cell 2015 Dec 14;28(6):831-833. PMID: 24856586.
- Zheng X, Carstens JL, Kim J, Scheible M, Kaye J, Sugimoto H, Wu CC, LeBleu VS, Kalluri R. Epithelial-to-mesenchymal transition is dispensable for metastasis but induces chemoresistance in pancreatic cancer. Nature 2015 Nov 26;527(7579):525-530. PMID: 26560028.
- Chen Y, LeBleu VS, Carstens JL, Sugimoto H, Zheng X, Malasi S, Saur D, Kalluri R. Dualreporter genetic mouse models of pancreatic cancer identify an epithelial-to-mesenchymal transition-independent metastasis program. EMBO Mol Med. 2018 Aug 17. PMID: 30120146.
Tissue Injury, Repair and Regeneration
During renal fibrosis a partial epithelial-to-mesenchymal program results in loss of normal renal parenchyma function, contributing to the fibrotic process; this program can be genetically targeted to reverse established disease. The image depicts immunostaining of the organic anion transporter OAT3/SLC22A6 (pink) and nuclei (DAPI, cyan) in normal murine kidney tissue. © Nature Medicine
Cancer is a disease with two components: the genetic injury and the host response to repair and regenerate the damage to the organ. The dynamic balance of these two sides of ‘cancer coin’ determines the rate of cancer progression and metastasis. If the host response to genetic defects of cancer cells involves successful immune surveillance, extracellular matrix production and recruitment of repair and regenerative mesenchymal cells such as fibroblasts, cancer is controlled. However, cancer cells often subjugate such host responses to aid in the growth of the tumors. For the past two decades, our laboratory invested substantial intellectual energy to discover the principles governing the tissue injury and regeneration responses associated with autoimmune and genetic kidney diseases, organ fibrosis, embryonic development, pregnancy disorders, and wound healing. The comprehensive knowledge gained from such studies had a direct impact on the unraveling new biology associated with host response to cancer. Keeping the ultimate translational goals in mind, the current projects are designed to discover the governing principles of immune recognition of damaged parenchymal cells in the context chronic diseases such as organ fibrosis and cancer, and to decipher the functional heterogeneity of fibrosis-associated fibroblasts when compared with carcinoma-associated fibroblasts. Identification of functional differences in the pathogenic extracellular matrix between neoplastic and non-neoplastic diseases is offering novel insights into regulation of tumor growth and dissemination, and regulation of tumor immunity. Studies related to placental hypoxia and cytotrophoblast invasion are providing new clues as to how tumor hypoxia regulates cancer invasion and metastasis.
Relevant Publications:
- Kalluri R. The biology and function of fibroblasts in cancer. Nature Rev Cancer 2016 Aug 23;16(9):582-98. PMID: 27550820.
- Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R. BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nature Medicine 2003 Jul;9(7):964-8. PMID: 12808448.
- Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R. Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nature Medicine 2007 Aug;13(8):952-61. PMID: 17660828.
- Sugimoto H, LeBleu VS, Bosukonda D, Keck P, Taduri G, Bechtel W, Okada H, Carlson W Jr, Bey P, Rusckowski M, Tampe B, Tampe D, Kanasaki K, Zeisberg M, Kalluri R. Activin-like kinase 3 is important for kidney regeneration and reversal of fibrosis. Nature Medicine 2012 Feb 5;18(3):396-404. PMID: 22306733.
- LeBleu VS, Taduri G, O'Connell J, Teng Y, Cooke VG, Woda C, Sugimoto H, Kalluri R. Origin and function of myofibroblasts in kidney fibrosis. Nature Medicine 2013 Aug;19(8):1047-53. PMID: 23817022
- Lovisa S, LeBleu VS, Tampe B, Sugimoto H, Vadnagara K, Carstens JL, Wu CC, Hagos Y, Burckhardt BC, Pentcheva-Hoang T, Nischal H, Allison JP, Zeisberg M, Kalluri R. Epithelial-to-mesenchymal transition induces cell cycle arrest and parenchymal damage in renal fibrosis. Nature Medicine 2015 Sep;21(9):998-1009. PMID: 26236991.
Extracellular Vesicles in Health and Disease
Exosomes are extracellular vesicles of ~40-160nm in size and released by all cells of the human body, and all cells of the animal and plant kingdom. Our laboratory is interested in identifying the physiological function of exosomes and their role in disease states such as cancer. In the last five years, we unraveled new biology associated with exosomes. We identified functional mRNA and microRNAs in exosomes and discovered that cancer exosomes can perform cell-independent microRNA biogenesis, which aid in the transformation of normal epithelial cells. We demonstrated that cancer-derived exosomes could induce non-tumorigenic epithelial cells to form tumors, and we are currently evaluating the mechanism(s) behind such oncogenic potential of cancer exosomes. Our laboratory identified double stranded genomic DNA in cancer exosomes and established their utility in diagnosis of cancer. We also exploited the property of exosomes to enter other cells and identified methods to deliver cancer drug to tumors. We demonstrate the capacity of engineered exosomes to target oncogenic Kras in pancreatic cancer (iExosomes). This discovery was translated into pre-clinical studies employing organoids, patient derived xenografts, and genetically engineered mouse models of pancreatic cancer. Good manufacturing practice produced iExosomes are being moved into Phase I testing at the MD Anderson Cancer Center. Current projects are employing CRISPR-Cas9 screens to identify novel pathways associated with exosomes production/release and uptake by other cells, and to identify novel biology that can be exploited for diagnosis and treatment of cancer and other diseases.
Relevant publications:
- Melo SA, Sugimoto H, O'Connell JT, Kato N, Villanueva A, Vidal A, Qiu L, Vitkin E, Perelman LT, Melo CA, Lucci A, Ivan C, Calin GA, Kalluri R. Cancer exosomes perform cell-independent microRNA biogenesis and promote tumorigenesis. Cancer Cell 2014 Nov 10;26(5):707-21. PMID: 25446899
- Kahlert C, Melo SA, Protopopov A, Tang J, Seth S, Koch M, Zhang J, Weitz J, Chin L, Futreal A, Kalluri R. Identification of double-stranded genomic DNA spanning all chromosomes with mutated KRAS and p53 DNA in the serum exosomes of patients with pancreatic cancer. J Biol Chem 2014 Feb 4;289(7):3869-75. PMID: 24398677
- Melo SA, Luecke LB, Kahlert C, Fernandez AF, Gammon ST, Kaye J, LeBleu VS, Mittendorf EA, Weitz J, Rahbari N, Reissfelder C, Pilarsky C, Fraga MF, Piwnica-Worms D, Kalluri R. Glypican-1 identifies cancer exosomes and detects early pancreatic cancer. Nature 2015 Jul 9;523(7559):177-82.
- Kamerkar S, LeBleu VS, Sugimoto H, Yang S, Ruivo CF, Melo SA, Lee JJ, Kalluri R. Exosomes facilitate therapeutic targeting of oncogenic KRAS in pancreatic cancer. Nature 2017 Jun 22;546(7659):498-503. PMID: 26106858.
- Mendt M, Kamerkar S, Sugimoto H, McAndrews KM, Wu CC, Gagea M, Yang S, Blanko EVR, Peng Q, Ma X, Marszalek JR, Maitra A, Yee C, Rezvani K, Shpall E, LeBleu VS, Kalluri R. Generation and testing of clinical-grade exosomes for pancreatic cancer. JCI Insight 2018 Apr 19;3(8). PMID: 29669940
Cancer Without Disease
A Novel and Practical Strategy for Prevention and Control of Malignant Cancer
Cancer is commonly understood to be a collection of diseases causing functional abnormality, often severe and life-threatening. However, cancer is not always associated with lethal disease. Many cancers remain a contained and dormant group of abnormal cells, never becoming invasive, malignant, or clinically relevant leading to a disease. Kept dormant, these cancers could be managed like other chronic conditions, and the word ‘cancer’ would not be considered a death sentence. The future of oncology will therefore challenge and redefine cancer classification and treatment strategies, including introducing new approaches to keep cancer contained, stave off clinical illness, and outlive the disease resulting from cancer.
It is likely that up to 35% of adults over the age of 40 may already have these genetically defined, contained cancers, or carcinoma in-situ. Individuals with these lesions can be considered as having ‘cancer without disease’. While some in-situ cancers may progress to require treatment, many remain clinically silent over an individual’s lifespan, enabling them to live in continued good health with prolonged lifespan. Due to advanced molecular tools and imaging capabilities, detection of these contained cancers is becoming more common, but carries the risk of overdiagnosis and overtreatment. Unnecessary treatment of these lesions is not without harm, exposing patients to physical and financial toxicity and diminished quality of life. Strategies to maintain cancer without the disease are critically needed, and potentially within reach.
Cancer Without Disease
Raghu Kalluri, M.D., Ph.D.
Principal Investigator
Kalluri Laboratory
The next leap forward in cancer treatment will see cancer and health co-exist.
Success rests on our understanding of the biological mechanisms that prevent progression to invasive cancer and resultant clinical disease. Increasing age is the number one risk factor for developing the disease of cancer due to accumulation of cellular and genetic damage, and the simultaneous compromise of immune and damage-repair functions. Fundamental discovery research in the Kalluri Laboratory seeks to uncover novel strategies to diagnostically and therapeutically circumvent such vulnerabilites to prolong healthy years, with healthy organ function, and significantly delay emergence of malignant cancer. Results of our studies will inform novel cancer control interventions.