Phosphorylation-mediated activation of LDHA promotes cancer cell invasion and tumour metastasis.

Metastases remain the major cause of death from cancer. Recent molecular advances have highlighted the importance of metabolic alterations in cancer cells, including the Warburg effect that describes an increased glycolysis in cancer cells. However, how this altered metabolism contributes to tumour metastasis remains elusive. Here, we report that phosphorylation-induced activation of lactate dehydrogenase A (LDHA), an enzyme that catalyses the interconversion of pyruvate and lactate, promotes cancer cell invasion, anoikis resistance and tumour metastasis. We demonstrate that LDHA is phosphorylated at tyrosine 10 by upstream kinases, HER2 and Src. Targeting HER2 or Src attenuated LDH activity as well as invasive potential in head and neck cancer and breast cancer cells. Inhibition of LDH activity by small hairpin ribonucleic acid or expression of phospho-deficient LDHA Y10F sensitized the cancer cells to anoikis induction and resulted in attenuated cell invasion and elevated reactive oxygen species, whereas such phenotypes were reversed by its product lactate or antioxidant N-acetylcysteine, suggesting that Y10 phosphorylation-mediated LDHA activity promotes cancer cell invasion and anoikis resistance through redox homeostasis. In addition, LDHA knockdown or LDHA Y10F rescue expression in human cancer cells resulted in decreased tumour metastasis in xenograft mice. Furthermore, LDHA phosphorylation at Y10 positively correlated with progression of metastatic breast cancer in clinical patient tumour samples. Our findings demonstrate that LDHA phosphorylation and activation provide pro-invasive, anti-anoikis and pro-metastatic advantages to cancer cells, suggesting that Y10 phosphorylation of LDHA may represent a promising therapeutic target and a prognostic marker for metastatic human cancers.

CT Accuracy of Extrinsic Tongue Muscle Invasion in Oral Cavity Cancer.

BACKGROUND AND PURPOSE: Extrinsic tongue muscle invasion in oral cavity cancer upstages the primary tumor to a T4a. Despite this American Joint Committee on Cancer staging criterion, no studies have investigated the accuracy or prognostic importance of radiologic extrinsic tongue muscle invasion, the feasibility of standardizing extrinsic tongue muscle invasion reporting, or the degree of agreement across different disciplines: radiology, surgery, and pathology. The purpose of this study was to assess the agreement among radiology, surgery, and pathology for extrinsic tongue muscle invasion and to determine the imaging features most predictive of extrinsic tongue muscle invasion with surgical/pathologic confirmation. MATERIALS AND METHODS: Thirty-three patients with untreated primary oral cavity cancer were included. Two head and neck radiologists, 3 otolaryngologists, and 1 pathologist prospectively evaluated extrinsic tongue muscle invasion. RESULTS: Fourteen of 33 patients had radiologic extrinsic tongue muscle invasion; however, only 8 extrinsic tongue muscle invasions were confirmed intraoperatively. Pathologists were unable to determine extrinsic tongue muscle invasion in post-formalin-fixed samples. Radiologic extrinsic tongue muscle invasion had 100% sensitivity, 76% specificity, 57% positive predictive value, and 100% negative predictive value with concurrent surgical-pathologic evaluation of extrinsic tongue muscle invasion as the criterion standard. On further evaluation, the imaging characteristic most consistent with surgical-pathologic evaluation positive for extrinsic tongue muscle invasion was masslike enhancement. CONCLUSIONS: Evaluation of extrinsic tongue muscle invasion is a subjective finding for all 3 disciplines. For radiology, masslike enhancement of extrinsic tongue muscle invasion most consistently corresponded to concurrent surgery/pathology evaluation positive for extrinsic tongue muscle invasion. Intraoperative surgical and pathologic evaluation should be encouraged to verify radiologic extrinsic tongue muscle invasion to minimize unnecessary upstaging. Because this process is not routine, imaging can add value by identifying those cases most suspicious for extrinsic tongue muscle invasion, thereby prompting this more detailed evaluation by surgeons and pathologists.

RSK2 signals through stathmin to promote microtubule dynamics and tumor metastasis.

Metastasis is responsible for >90% of cancer-related deaths. Complex signaling in cancer cells orchestrates the progression from a primary to a metastatic cancer. However, the mechanisms of these cellular changes remain elusive. We previously demonstrated that p90 ribosomal S6 kinase 2 (RSK2) promotes tumor metastasis. Here we investigated the role of RSK2 in the regulation of microtubule dynamics and its potential implication in cancer cell invasion and tumor metastasis. Stable knockdown of RSK2 disrupted microtubule stability and decreased phosphorylation of stathmin, a microtubule-destabilizing protein, at serine 16 in metastatic human cancer cells. We found that RSK2 directly binds and phosphorylates stathmin at the leading edge of cancer cells. Phosphorylation of stathmin by RSK2 reduced stathmin-mediated microtubule depolymerization. Moreover, overexpression of phospho-mimetic mutant stathmin S16D significantly rescued the decreased invasive and metastatic potential mediated by RSK2 knockdown in vitro and in vivo. Furthermore, stathmin phosphorylation positively correlated with RSK2 expression and metastatic cancer progression in primary patient tumor samples. Our finding demonstrates that RSK2 directly phosphorylates stathmin and regulates microtubule polymerization to provide a pro-invasive and pro-metastatic advantage to cancer cells. Therefore, the RSK2-stathmin pathway represents a promising therapeutic target and a prognostic marker for metastatic human cancers.

Accuracy of Preoperative Imaging in Detecting Nodal Extracapsular Spread in Oral Cavity Squamous Cell Carcinoma.

BACKGROUND AND PURPOSE: The increasing impact of diagnosing extracapsular spread by using imaging, especially in patients with oropharyngeal squamous cell carcinoma, highlights the need to rigorously evaluate the diagnostic accuracy of imaging. Previous analysis suggested 62.5%-80.9% sensitivity and 60%-72.7% specificity. Our goals were to evaluate the accuracy of imaging in diagnosing extracapsular spread in a cohort of patients with oral cavity squamous cell carcinoma (pathologic confirmation of extracapsular spread routinely available), as a proxy for oropharyngeal squamous cell carcinoma, and to independently assess the reliability of imaging features (radiographic lymph node necrosis, irregular borders/stranding, gross invasion, and/or node size) in predicting pathologically proven extracapsular spread. MATERIALS AND METHODS: One hundred eleven consecutive patients with untreated oral cavity squamous cell carcinoma and available preoperative imaging and subsequent lymph node dissection were studied. Two neuroradiologists blinded to pathologically proven extracapsular spread status and previous radiology reports independently reviewed all images to evaluate the largest suspicious lymph node along the expected drainage pathway. Radiologic results were correlated with pathologic results from the neck dissections. RESULTS: Of 111 patients, 29 had radiographically determined extracapsular spread. Pathologic examination revealed that 28 of 111 (25%) had pathologically proven extracapsular spread. Imaging sensitivity and specificity for extracapsular spread were 68% and 88%, respectively. Radiographs were positive for lymph node necrosis in 84% of the patients in the pathology-proven extracapsular spread group and negative in only 7% of those in the pathologically proven extracapsular spread-negative group. On logistic regression analysis, necrosis (P = .001), irregular borders (P = .055), and gross invasion (P = .068) were independently correlated with pathologically proven extracapsular spread. CONCLUSIONS: Although the specificity of cross-sectional imaging for extracapsular spread was high, the sensitivity was low. Combined logistic regression analysis found that the presence of necrosis was the best radiologic predictor of pathologically proven extracapsular spread, and irregular borders and gross invasion were nearly independently significant.