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McMahon Lab


Director of Professional Education; and Co-Leader, Developmental Therapeutics Program, UCSF Helen Diller Family Comprehensive Cancer Center
Efim Guzik Distinguished Professorship in Cancer Biology, UCSF

Full Biosketch: Martin McMahon, PhD
Professor In Residence, Department of Anatomy, UCSF


(415) 502-1317 (lab)
(415) 502-3179 (fax)

1450 3rd St., MC 0128; PO Box 589001
San Francisco, CA 94158-9001

deliveries: 1450 3rd Street, HD-340; San Francisco, CA 94158


Research Summary

Cancer research in Martin McMahon’s lab is focused on the role of RAS-regulated signal transduction pathways in the aberrant behavior of melanoma, thyroid, pancreas and lung cancer using in vivo mouse model systems complemented by in vitro cell culture systems. RAS-family GTPases transmit signals throughout the cell via activation of cytosolic signal transduction pathways. Prominent among these is the RAF-MEK-ERK MAP kinase and the PI3’-kinase-PDK-AKT signaling pathways. These pathways are linked to human cancer both by their regulation by human RAS oncogenes and by evidence of somatic mutations in BRAF, PIK3CA or PTEN, which occur in a range of human malignancies. Mutated RAS is detected in ~25% of all human malignancies, whereas mutational activation of BRAF or PIK3CA is less common. However, in some diseases like melanoma or papillary thyroid cancer, mutational activation of BRAF is far more common than alterations in RAS. Indeed, mutation of BRAF is the earliest and most frequent somatic mutation known to occur in melanoma. Although the genetics of melanoma, thyroid, pancreas and lung cancer have been explored in some detail, there is a large gulf in our understanding of how mutations in oncogenes and tumor suppressors influence the aberrant behavior of cancer cells. Furthermore, since mutationally activated RAS proteins have proven to be intractable pharmacological targets, there is an urgent need for new therapeutic approaches to target critical RAS effector pathways to treat cancers in which RAS or its downstream effectors are required for tumor maintenance. Consequently we are employing genetic, biochemical and pharmacological approaches to understand the role of oncogenes and tumor suppressors in the initiation, progression and maintenance of melanoma, thyroid, pancreas and lung cancer1-4. We are taking the following approaches to explore fundamental aspects of the cell and molecular biology of these diseases:

Mouse models of BRAFV600E-Induced Lung Cancer

To explore cancer initiation and progression by mutationally activated BRAFV600E in a relevant in vivo setting, we generated BRafCA mice in which the expression of oncogenic BRAFV600E can be induced in a temporally and spatially restricted manner by the action of Cre recombinase1. Using BRafCA mice we have generated mouse models of BRAFV600E-induced melanoma2, lung1, thyroid3 and pancreas4 cancer. We are now using BRafCA and similarly designed KRasLSL mice from Tyler Jacks to conduct a head-to-head comparison between oncogenic KRASG12D and BRAFV600E in the transformation of lung epithelial cells in vivo. In addition, we are using mouse models of KRASG12D- or BRAFV600E-induced lung tumorigenesis to test the anti-tumor efficacy of therapeutics that inhibit RAF-MEK-ERK or PI3’-kinase-PDK-AKT signaling. Finally, we are exploring the mechanism(s) by which mutationally activated forms of BRAF and PIK3CA cooperate in lung tumorigenesis.

Mechanisms of Oncogene-Induced Senescence

Whereas the action of proto-oncogenes such as RAS or BRAF is generally associated with the promotion of cell proliferation, there is clear evidence that oncogenic forms of RAS or BRAF can elicit anti-proliferative responses known as oncogene-induced senescence (OIS)5. It is thought that OIS is a cellular defense mechanism that shunts initiated tumor cells into a non-dividing state thereby protecting the organism from cancer. Only by undermining the mechanism(s) of OIS can initiated cells show cancer progression. Using our BRafCA mouse model we are exploring the mechanism(s) of BRAFV600E-induced senescence and how alterations in tumor suppressors such as PTEN, INK4A/ARF or TP53 allow escape from BRAFV600E-induced senescence. 

Mouse models of BRAFV600E-Induced Melanoma

Using compound Tyrosinase::CreER; BRafCA mice we have generated mouse models of malignant melanoma2. Upon melanocyte specific expression of BRAFV600E, mice developed benign melanocytic hyperplasias that failed to progress to melanoma over 15-20 months. By contrast, expression of BRAFV600E combined with silencing of either the PTEN or the INK4A/ARF tumor suppressors led to development of metastatic melanoma with 100% penetrance and short latency with metastases observed in lymph nodes and lungs. Melanoma was prevented by either by pharmacological inhibition of mTorc1 or MEK1/2 respectively. These mice, engineered with a common genetic profile to human melanoma, are an excellent model system for the study of melanoma’s cardinal feature of metastasis and for the pre-clinical evaluation of agents designed to prevent or treat metastatic disease.

Regulation of apoptosis by mutationally activated BRAF or PIK3CA

Mutationally activated BRAF or NRAS are expressed in the vast majority of melanomas and serve to promote the cell cycle and suppress apoptosis. Suppression of apoptosis is accompanied by inhibition of expression of BIM and BMF, two related pro-apoptotic members of the BCL-2 family6. We are exploring the biochemical mechanisms by which BRAF activation regulates BIM and BMF expression using cultured melanoma cells derived from our BRafCA melanoma mouse model (see above) and bona fide human melanoma derived cell lines. Although there is strong genetic and biochemical evidence for an important role for BRAF signaling in the initiation and progression of human melanoma, and for BIM and BMF in the regulation of melanocyte survival, we will test the hypothesis that these proteins are linked in a direct biochemical pathway. In addition, we are exploring whether the elevated expression of BIM or BMF is required for the anti-tumor efficacy of pharmacological agents that target the BRAFV600E-MEK-ERK pathway.

Mouse model of thyroid cancer

Using compound Thyroglobulin::CreER; BRafCA mice we have generated a new mouse model of adult onset thyroid cancer3. We are currently using these mice to explore the ability of oncogenic BRAFV600E to cooperate with genetic alterations in PIK3CA or PTEN to promote the transition of benign papillary thyroid cancer (PTC) to more aggressive anaplastic thyroid cancer (ATC). In addition, we are employing pathway-targeted therapeutics to design new regimens of thyroid cancer therapy. In that regard, we are particularly interested in testing whether inhibition of BRAFV600E→MEK→ERK signaling will synergize with radioactive I[131] through induced expression of the Sodium-Iodide Symporter (NIS).


1. Dankort et al. (2007) A new mouse model to explore the initiation, progression and therapy of BRAFV600E-induced lung tumors. Genes Dev. 21: 379-385

2. Dankort et al., (2009) BRAFV600E cooperates with PTEN silencing to induce metastatic melanoma Nature Genetics 41: 544-52.

3. Charles et al., (2011) Mutationally activated BRAFV600E elicits papillary thyroid cancer in the mouse Cancer Research 71: 3863-71

4. Collisson et al., (2011) A Central Role for RAF-MEK-ERK Signaling in the Genesis of Pancreatic Ductal Adenocarcinoma. Science Translational Medicine (Under Review)

5. Zhu et al. (1998) Senescence of human fibroblasts induced by oncogenic Raf. Genes. Dev. 12: 2997-3007

6. Cartlidge et al., (2008) Anti-apoptotic effect of BRAF→MEK→ERK signaling in melanocytes and melanoma cells is mediated by suppression of BIM expression. Pigment Cell and Melanoma Research 21: 534-544