Viale Laboratory

Dissection of Tumor Complexity and Functional Heterogeneity

A long-standing concept in cancer biology is that tumors are extremely complex, characterized by extraordinary intratumor heterogeneity. This inherent complexity has critical implications, underscoring the adaptability of cancer cells to perturbations. To unravel adaptive mechanisms and understand the contributions of different subclones to tumor expansion, dissemination, and treatment resistance, we recently developed Clonal Replica Tumors (CRTs), an innovative platform to study heterogeneous cell populations and their complex clonal dynamics in vivo (PMID: 34529467; PMID: 38478609). CRTs leverage identical clonal compositions in orthotopic cohorts derived from human and mouse cancers, enabling longitudinal studies to comprehensively capture with unparalleled precision clonal dynamics in response to both intrinsic and external perturbations (e.g. hypoxia, nutrient availability, physical constraints, evolving microenvironment and therapies). Furthermore, this approach allows spatial reconstruction of tumor clonal architecture and insight into the dynamic interactions between tumor subclones and their evolving microenvironment.

Physiological Functions of Cancer-Associated Genomic Aberrations

Cancer is widely described as a genetic disease, however, mutations and complex genomic events typical of cancer cells are also found in normal tissues. How normal cells and tissues accumulate and tolerate mutations and aneuploidy while maintaining differentiation and functionality is a question our lab actively explores. Specifically, do mutations and genomic alterations serve any physiological roles in adult tissues? Recently, while studying tissue regeneration during acute pancreatic damage, we uncovered an unrecognized “beneficial” role of oncogenic KRAS mutations in preserving tissue integrity. Our findings suggest that constitutive activation of KRAS signaling ameliorates pancreatic damage during repeated inflammation, indicating a potential selective advantage for cells with KRAS-activating mutations, which may explain why KRAS is the universal driver of pancreatic cancer (PMID: 34529467). These insights imply that cancer-associated mutations may play physiological roles in maintaining tissue functionality in response to damage and that positive selection for mutations in cancer driver genes may occur long before oncogenesis for reasons unrelated to tumor development.

Early Determinants of Tumor Progression

The association between tumors and inflammation is a well-established clinical observation, with pancreatic cancer in particular exemplifying the cooperation between inflammation and activated oncogenes. Multiple experimental models have shown that inflammation accelerates tumor progression and cooperates with KRAS activation to induce neoplastic precursor lesions. However, our studies suggest a more complex role of inflammation in tumor development, as an active inflammatory environment is not necessary for tumor progression. Transient inflammation, in fact, can promote tumorigenesis long after resolution through persistent transcriptional deregulation and epigenetic changes in epithelial cells, a phenomenon we term "epithelial memory" (PMID: 34529467). To better understand the molecular mechanisms underlying epithelial cell reprogramming and counteract the detrimental effects of this memory on tumorigenesis, our lab is exploring the effects of various inflammatory damages, including those from obesity, microplastics and environmental chemicals.