For the past 17 years, my laboratory has focused on elucidating the cellular and molecular pathophysiology of aero-digestive tract cancers, particularly squamous cell carcinomas of the head-&-neck, lung and esophagus. Our most important contributions have revolved around the role of the Transforming Growth Factor-ß (TGFß) signaling pathway in squamous carcinogenesis. Because TGFß appears to play similar roles in many cancers, we have expanded our disease focus to include breast-, colon-, endometrial- and cervical cancer.

We have made a number of important contributions to our understanding of how these cancers escape from normal physiological cell cycle control and regulation of differentiation by TGFß. We were among the first to identify TGFß as an extremely potent physiological auto- and/or paracrine inhibitor of cell cycle progression in normal keratinocytes (the cell of origin of squamous cell carcinomas). We then showed that most common carcinomas are refractory to TGFß-mediated cell cycle arrest.

Because the escape from TGFß control appears to be critical for cancer development, we have focused most of our recent efforts on elucidating the molecular mechanisms underlying this escape. We were the first to show that TGFß resistance is the result of gene inactivation. One of our most important findings is that intragenic mutations can occur in the TGFß type II as well as type I receptors (TßR). Moreover, these TßR mutants are defective in terms of their signaling ability . Since then, we extended these studies to determine the spectrum of genetic alterations of the TßR genes in aero-digestive tract cancers as well as in other TGFß-refractory common human neoplasms. Thus far, our studies of the TßR-II gene in primary tumor specimens have shown that, although missense or nonsense mutations are probably relatively uncommon, loss of mRNA- or protein expression occurs at much higher frequency in esophageal-, endometrial and small-cell lung cancers.

Our current strategy is to develop the tools that will allow us to identify, in individual primary cancers, the specific molecular lesion that has resulted in TGFß resistance. In addition, we are studying the biological significance of TGFß resistance using tissue microarray technology. For example, it is likely that TGFß-refractory cancers are more invasive and/or metastatic, and perhaps more resistant to therapy than TGFß-responsive cancers. Last but not least, we now have all of the reagents and technology in place to embark on a major new project to develop a novel form of cancer therapy based on inhibition of TGFß signaling. This idea is based on the overwhelming experimental evidence that many cancers produce large amounts of bioactive TGFß that enhance their ability to invade and metastasizes, stimulate angiogenesis and suppress anti-tumor immunity. By blocking these effects of tumor-derived TGFß on normal cells in their microenvironment, we hope to significantly complement and potentiate the efficacy of conventional cytotoxic forms of cancer therapy. Specifically, we are testing the activity of selective and potent inhibitors of TGFß receptor kinases using a number of specific in vitro and in vivo assays, with the ultimate goal of taking the most promising and safest of these compounds into clinical trial.

	Selective inhibitors of type I receptor kinase block cellular transforming growth factor-beta signaling. Ge R, Rajeev V, Subramanian G, Reiss KA, Liu D, Higgins L, Joly A, Dugar S, Chakravarty J, Henson M, McEnroe G, Schreiner G, Reiss M. Biochem Pharmacol. 2004 Jul 1;68(1):41-50.
	A prototype for unsupervised analysis of tissue microarrays for cancer research and diagnostics. Chen W, Reiss M, Foran DJ. IEEE Trans Inf Technol Biomed. 2004 Jun;8(2):89-96.
	Ovarian cancer detection by logical analysis of proteomic data. Alexe G, Alexe S, Liotta LA, Petricoin E, Reiss M, Hammer PL. Proteomics. 2004 Mar;4(3):766-83.
	Transforming growth factor-beta 1 regulation of collagenase-3 expression in osteoblastic cells by cross-talk between the Smad and MAPK signaling pathways and their components, Smad2 and Runx2. Selvamurugan N, Kwok S, Alliston T, Reiss M, Partridge NC. J Biol Chem. 2004 Apr 30;279(18):19327-34. Epub 2004 Feb 24.