Liver Carcinogenesis Section
Xin Wei Wang, Ph.D.
Research Program and Goals
Our laboratory is interested in studying genetics, genomics and biochemical pathways related to human cancer. Primary liver cancer is the second most deadly cancer in men and fifth most prevalent cancer worldwide (estimated 695,900 deaths in 2008), with a recent sharp increase of incidence in the United States. Hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) are two major types of primary liver cancer. Chronic liver diseases such as viral hepatitis caused by infection with hepatitis B and C viruses (HBV or HCV), alcohol consumption, or obesity, are major global health burdens that can increase the risk of HCC and ICC. Despite great progress in the diagnosis and development of new treatment modalities, the improvement in cancer mortality is very modest. These diseases remain the most difficult-to-treat malignancies, with a 5-year survival rate of less than 12% in the United States.
We are exploring molecular mechanisms related to primary liver cancer to learn how cancer cells initiate and metastasize, and to identify biomarkers useful for early diagnosis and molecular targets for effective therapy. Currently, we are focusing on two main complementary research projects with an objective to change the current status quo.
Current Research Projects
1. Dissecting molecular heterogeneity of liver cancer to improve outcome among diverse populations.
Like other lethal solid tumors, most primary liver cancer patients are considered incurable due to extensive tumor heterogeneity. Both inter-tumor and intra-tumor heterogeneity have been recognized, possibly emanating from the presence of cancer stem cells or selection by clonal evolution. Cancer genomic heterogeneity thereby results in varying degrees of clinical presentation and tumor biology, which impedes treatment options and poses a significant challenge to cancer management.
The outcome of liver cancer patients in particular, has remained quite poor. Surgical resection of small HCC, when clinically identified early enough, may be potentially effective. However, up to 80% of these patients develop recurrent tumors after 5 years. Although molecularly targeted therapies are promising new treatment modalities, their effectiveness has only shown promise at the statistical level but has not fundamentally reduced overall mortality. Thus, our ability to identify distinct groups of cancer patients with similar tumor biology who are most likely to respond to a specific therapy would have a significant impact on improving patient outcome.
To overcome this problem, our laboratory has applied molecular-based technologies including genomic, transcriptomic and metabolomic profiling of liver specimens among diverse populations to identify discrete tumor subgroups with unique tumor biology. Consequently, we have developed various genome-based signatures linked to venous metastasis, tumor recurrence, p53 mutations, stem cell features, male dominance or treatment response. These signatures have also been shown to be useful as diagnostic or prognostic tools to discriminate patients with greater homogeneity, assist in molecular re-staging, predict outcome or guide treatment, and to identify clinically relevant therapeutic targets.
2. Integrated genomics to identify drivers of human liver cancers.
We are interested in identifying key driver genes and their signaling mechanisms responsible for tumor initiation and progression. Since human malignancies share a set of common cancer hallmarks, key genes responsible for each hallmark in principle are ideal targets for targeted therapies. However, each cancer has a unique set of compromised genomic loci. A combination of different cancer hallmarks can result in new convergent molecular networks that are unique to each type of tumor. It is a challenge to identify such a distinct molecular node for which the growth of a particular type of tumor is dependent on.
We hypothesize that integrated genomics through a combination of mutations, somatic copy number alteration (SCNA), and methylome, transcriptome and metabolome profiling to study tumor specimens with well-defined phenotypic spectra can uncover key cancer driver genes and delineate their critical gatekeepers of cancer initiation and progression. For example, using high-resolution, array-based comparative genomic hybridization and transcriptome analysis of HCC samples, we have identified several novel tumor suppressor genes on chromosome 8p associated with HCC progression and patient prognosis. We have also identified shared molecular nodes as potential therapeutic targets among HCC and ICC samples through integrated mRNA and microRNA profiling. In addition, global microRNA and mRNA profiling of a subset of HCC samples with stem cell features allowed us to identify a critical microRNA player in hepatic cancer stem cells. Moreover, we have identified several druggable targets such as osteopontin, beta-catenin, EpCAM and miR-181, which may be used to eliminate liver cancer cells or reduce metastatic progression.
We believe this approach is powerful in identifying key driver genes, providing numerous insights into our understanding of cancer cell origin and its molecular mechanisms, challenging the current paradigm of tumor evolution and offering improvements to patient management.
Tumor Cell Biodiversity Drives Microenvironmental Reprogramming in Liver Cancer
On the cover: Liver cancers are molecularly and biologically heterogenous, which contributes to their therapeutic failures and lethal outcomes. Ma et al. (pp. 418–430) have developed a single-cell-based approach to determine tumor cell communities (depicted as dice emptying out of a jar) and uncover a unique liver cancer ecosystem relevant to immune therapy. A tumor cell community is depicted by dice with different colors and shapes, where color represents cell type and shape represents unique molecular properties. Artwork by Ethan Tyler.
Ma L, Hernandez MO, Zhao Y, Mehta M, Tran B, Kelly M, Rae Z, Hernandez JM, Davis JL, Martin SP, Kleiner DE, Hewitt SM, Ylaya K, Wood BJ, Greten TF, Wang XW. Tumor cell biodiversity drives microenvironmental reprogramming in liver cancer. Cancer Cell 36(4): 418-30, 2019; PMID: 31588021.
TIGER-LC Consortium. Common Molecular Subtypes Among Asian Hepatocellular Carcinoma and Cholangiocarcinoma
On the cover: The Thailand Initiative in Genomics and Expression Research for Liver Cancer (TIGER-LC) Consortium (depicted as a tiger) emerges from foliage, representing molecular, clinical, and epidemiological studies from teams in the United States, Thailand, and Japan, to generate a multilayered genomic and genetic liver cancer data ecosystem (represented by the tiger’s tail). Although common molecular subtypes (depicted as bamboo stalks) are observed among liver cancer types, there are differences observed between Asian and Caucasian populations (depicted by different bamboo colors). For more details, see Chaisaingmongkol et al. (pp. 57–70). Cover art by Ethan Tyler.
Chaisaingmongkol J, Budhu A, Dang H, Rabibhadana S, Pupacdi B, Kwon SM, Forgues M, Bhudhisawasdi V, Lertprasertsuke N, Chotirosniramit A, Pairojkul C, Auewarakul CU, Sricharunrat T, Phornphutkul K, Sangrajrang S, Cam M, He P, Hewitt SM, Ylaya K, Wu X, Andersen JB, Thorgeirsson SS, Waterfall JJ, Zhu YJ, Walling J, Stevenson HS, Meltzer PS, Loffredo CA, Hama N, Shibata T, Wiltrout RH, Harris CC, Mahidol C, Ruchirawat M, Wang XW. Common molecular subtypes among Asian hepatocellular and cholangiocarcinoma. Cancer Cell 32(1): 57-70.e3, 2017; PMID: 28648284