William A. Weiss, MD, PhD

Professor
Department of Neurology
+1 415 502-1694
Research Overview: 

We develop and use in-vivo for neural cancers to:

  1. Identify genetic events that promote tumorigenesis.
  2. Study cancer stem and progenitor cells.
  3. Evaluate new targets, chemical genetic approaches, and mechanistic rationales for combining targeted agents.

Stem cell biology, genetics, and developmental therapeutics in glioma. Aberrant EGFR signaling features prominently in glioma, the most common primary adult brain tumor. We generated a mouse model for glioma by over-expressing EGFR under the S100 beta promoter (Weiss, 2003). Expression of oncogenes in rare cancer-stem-like cells in the subventricular zone led to differentiation block and aberrant glial differentiation, resulting in astrocytoma (Persson, In revision). In contrast, murine oligodendrogliomas arose from abundant oligodendroglial progenitors in white matter. We described a progenitor origin for this more favorable form of glioma, demonstrating that a progenitor rather than a stem-cell origin underlies the improved outcome in patients (Persson, 2010). We were among the first to describe oncogene addiction driven by activated EGFR (Fan, 2002).  We described and characterized dual inhibitors of PI3K and mTOR, demonstrating that these drugs blocked mTOR inhibitor-driven activation of Akt, that EGFR signaling to Akt was dispensable for arrest, that EGFR signaling to Protein Kinase C alpha was central to the ability of PI3K to signal to mTOR, and that blockade of PI3K, mTOR and autophagy converted cytostatic PI3K/mTOR inhibitors into cytotoxic agents (Fan, 2006-2010). Activated alleles of EGFR occur in brain and lung-cancers, yet EGFR inhibitors benefit only lung cancer. We traced this differential response to lower occupancy rates of EGFR inhibitors in brain as compared to lung cancer mutants (Barkovich 2012).  EGFR is frequently co-amplified with EGFRvIII. We showed co-expression of EGFR and vIII in individual cells in human tumors, that vIII is a substrate for EGFR, and that co-expression drives STAT signaling (Fan et al, 2013).

Targeted expression of MYCN generate models of neuroblastoma and medulloblastoma in transgenic mice.  Neuroblastoma is the third most common tumor of childhood.  The proto-oncogene MYCN is amplified in 25% of neuroblastomas, marking incurable disease. We generated transgenic mice that mis-expressed MYCN in neural crest, that developed neuroblastoma, and that remain the standard GEM model used by the community (Weiss et al, 1997). Genome-wide screens revealed genetic alignment with human tumors (Weiss et al, 2002, Hackett et al, 2003). Through systems biology approaches, we identified altered neurotransmitter signaling through GABA as contributing to human and murine neuroblastoma, and described the alternative splicing landscape (Hackett et al, in revision; Chen et al, in revision). Murine neuroblastoma tumors mutant at p53 were resistant to chemotherapy, and modeled relapsed, drug-resistant neuroblastoma (Chesler, 2006-8). MYCN blockade reduced VEGF signaling, promoting vascular collapse (Chanthery, 2012). We synthesized and solved the co-crystal structure of a new class of MYCN-degrading drugs that drive an allosteric transition in Aurora Kinase A, blocking a kinase-independent stabilizing function of Aurora Kinase (Gustafson, 2014).  

MYCN is mis-expresssed in the majority of medulloblastoma tumors.  We used the Tet system to regulate MYCN expression and to image tumor-associated firefly luciferase expression in-vivo.  Targeted expression of MYCN to the brains of transgenic mice led to luciferase and MYCN-positive medulloblastoma, (Swartling, 2010). We also transduced MYCN into murine neural stem cells, separately cultured from prenatal or postnatal mice, with cells from hindbrain generating medulloblastoma, and from forebrain generating glioma. Orthotopic transduction of prenatal cerebellar stem cells drove SHH-dependent, while both prenatal brainstem and postnatal cerebellar stem cells drove SHH-independent disease (Swartling 2012).  Thus, distinct neural stem cell populations generated disparate brain tumors in response to MYCN. 

Genome-wide sequencing efforts have generally failed to identify new driver mutations for the majority of high-risk neuroblastoma and medulloblastoma.  In contrast, copy number analyses have identified recurrent regions of variation.  Regions of gain or loss on any human chromosome correspond to multiple different chromosomes in the mouse, which is challenging to model.  Thus, we are incorporating known driver mutations into engineered human induced pluripotent stem cells, to generate humanized mouse models for neuroblastoma and medulloblastoma.  These human based xenograft models generate a genetic platform critical both to test the importance of copy number variation in pathogenesis, and to develop therapies.

Primary Thematic Area: 
Cancer Biology & Cell Signaling
Secondary Thematic Area: 
Developmental & Stem Cell Biology
Research Summary: 
Mouse models and developmental therapeutics for neural cancers, particularly pediatric cancers
Mentorship Development: 

12/12/19    ACRA: Setting Training Expectations for Trainees on the Academic Career Track (1.5 hours)
2/18/21    Three Truths and Three Tries: Facing and Overcoming Critical Social Justice Challenges at the Micro, Mezzo, and Macro Levels

Websites

Publications: 

Clinical Significance and Molecular Annotation of Cellular Morphometric Subtypes in Lower Grade Gliomas discovered by Machine Learning.

Neuro-oncology

Liu XP, Jin X, Ahmadian SS, Yang X, Tian SF, Cai YX, Chawla K, Snijders AM, Xia Y, van Diest PJ, Weiss WA, Mao JH, Li ZQ, Vogel H, Chang H

Generation of immunocompetent syngeneic allograft mouse models for pediatric diffuse midline glioma.

Neuro-oncology advances

du Chatinier A, Meel MH, Das AI, Metselaar DS, Waranecki P, Bugiani M, Breur M, Simonds EF, Lu ED, Weiss WA, Garcia Vallejo JJ, Hoving EW, Phoenix TN, Hulleman E

Anti-GD2 synergizes with CD47 blockade to mediate tumor eradication.

Nature medicine

Theruvath J, Menard M, Smith BAH, Linde MH, Coles GL, Dalton GN, Wu W, Kiru L, Delaidelli A, Sotillo E, Silberstein JL, Geraghty AC, Banuelos A, Radosevich MT, Dhingra S, Heitzeneder S, Tousley A, Lattin J, Xu P, Huang J, Nasholm N, He A, Kuo TC, Sangalang ERB, Pons J, Barkal A, Brewer RE, Marjon KD, Vilches-Moure JG, Marshall PL, Fernandes R, Monje M, Cochran JR, Sorensen PH, Daldrup-Link HE, Weissman IL, Sage J, Majeti R, Bertozzi CR, Weiss WA, Mackall CL, Majzner RG