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Molecular architecture of cell regulation

The broad goal of our research is to contribute to uncovering the molecular nature of cell autonomous regulatory mechanisms permitting appropriate responses of human cells to their environment.

These mechanisms are ultimately responsible for initiating correct developmental and adaptive changes in cell behavior. Aberrant regulation of these mechanisms results in pathological changes that are responsible for initiating a wide variety of human diseases including cancer. Our focus has been on the contribution of Ras-family small GTPases to the regulation of proliferation, differentiation, and oncogenic transformation. Our work has shown that these proteins act as key nodes in signal transduction networks, integrating extracellular and intracellular cues to the activation of appropriate machinery driving the response of cells to those cues.

We are defining the composition, organization, and regulation of the Ras GTPase signaling network. We are using this information to establish paradigms describing the nature of signal-mediated information flow and connectivity to cell biological responses. With respect to human disease, we are translating our observations into a molecular understanding of the establishment of a minimal tumorigenic platform in general, and into defining the critical contribution of Ras oncogenes to initiation and maintenance of human cancer in particular.

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Cancer cell biology

Oncogenic corruption of basic cell biological systems supporting cell shape, organellar communication, and genomic stability is a fundamental trait governing pathological bypass of cell-autonomous restraints on proliferation and survival. 

Through mechanistic elaboration of adaptive membrane dynamics and biogenesis of catabolic organelles, we are helping to uncover some of the central principles that govern cellular homeostasis.  In particular, we are examining how nutrient-responsive orchestration of macromolecular protein complexes can specify adaptive modulation of cell growth versus self-renewal regulatory programs.

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Intervention target discovery

Diversity in the genetic lesions that drive cancer initiation and progression is extreme. This diversity exists not only among tumors from different patients, but also among cancer cells within the same patient. 

This nefarious complexity is, in large measure, responsible for the capacity of this disease to evade current best efforts for effective therapy. “Personalized medicine” has been proposed in response to this conundrum as a mechanism to tailor cancer treatment to a specific tumor’s genetic and epigenetic characteristics. However, selection of appropriate treatment is dramatically limited by the paucity of appropriate drugs and by the difficulty of linking treatment options to the appropriate patients.

The challenge is to identify authentic intervention targets for development of a sufficiently diverse cohort of therapies to contend with disease heterogeneity.  We are addressing this challenge by a focused investigation of common vulnerabilities that arise as a consequence of oncogene expression and tumor evolution. 

We have recognized the balanced role oncogenic perturbations in driving both disease progression and disease vulnerability. Interventions that disturb this balance could potentially be employed in jiu jitsu fashion to breach cancer cell tolerance of oncogenic corruption of proliferation and survival controls. 

We are employing a comprehensive approach, absent preconceived notions of mechanistic relationships, to develop the robust targets and chemical leads required to develop such interventions.

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