Cis-regulatory properties of medaka synexpression groups.

During embryogenesis, tissue specification is triggered by the expression of a unique combination of developmental genes and their expression in time and space is crucial for successful development. Synexpression groups are batteries of spatiotemporally co-expressed genes that act in shared biological processes through their coordinated expression. Although several synexpression groups have been described in numerous vertebrate species, the regulatory mechanisms that orchestrate their common complex expression pattern remain to be elucidated. Here we performed a pilot screen on 560 genes of the vertebrate model system medaka (Oryzias latipes) to systematically identify synexpression groups and investigate their regulatory properties by searching for common regulatory cues. We find that synexpression groups share DNA motifs that are arranged in various combinations into cis-regulatory modules that drive co-expression. In contrast to previous assumptions that these genes are located randomly in the genome, we discovered that genes belonging to the same synexpression group frequently occur in synexpression clusters in the genome. This work presents a first repertoire of synexpression group common signatures, a resource that will contribute to deciphering developmental gene regulatory networks.

Stress signaling in breast cancer cells induces matrix components that promote chemoresistant metastasis.

Metastatic progression remains a major burden for cancer patients and is associated with eventual resistance to prevailing therapies such as chemotherapy. Here, we reveal how chemotherapy induces an extracellular matrix (ECM), wound healing, and stem cell network in cancer cells via the c-Jun N-terminal kinase (JNK) pathway, leading to reduced therapeutic efficacy. We find that elevated JNK activity in cancer cells is linked to poor clinical outcome in breast cancer patients and is critical for tumor initiation and metastasis in xenograft mouse models of breast cancer. We show that JNK signaling enhances expression of the ECM and stem cell niche components osteopontin, also called secreted phosphoprotein 1 (SPP1), and tenascin C (TNC), that promote lung metastasis. We demonstrate that both SPP1 and TNC are direct targets of the c-Jun transcription factor. Exposure to multiple chemotherapies further exploits this JNK-mediated axis to confer treatment resistance. Importantly, JNK inhibition or disruption of SPP1 or TNC expression sensitizes experimental mammary tumors and metastases to chemotherapy, thus providing insights to consider for future treatment strategies against metastatic breast cancer.

Tenascin C in metastasis: A view from the invasive front.

The extracellular matrix protein tenascin C (TNC) is a large glycoprotein expressed in connective tissues and stem cell niches. TNC over-expression is repeatedly observed in cancer, often at the invasive tumor front, and is associated with poor clinical outcome in several malignancies. The link between TNC expression and poor survival in cancer patients suggests a role for TNC in metastatic progression, which is responsible for the majority of cancer related deaths. Indeed, functional studies using mouse models are revealing new roles of TNC in cancer progression and underscore its important contribution to the development of metastasis. TNC has a pleiotropic role in advancing metastasis by promoting migratory and invasive cell behavior, angiogenesis and cancer cell viability under stress. TNC is an essential component of the metastatic niche and modulates stem cell signaling within the niche. This may be crucial for the fitness of disseminated cancer cells confronted with a foreign environment in secondary organs, that can exert a strong selective pressure on invading cells. TNC is a compelling example of how an extracellular matrix protein can provide a molecular context that is imperative to cancer cell fitness in metastasis.